There is a great unmet need for pain therapies that are non-addictive and/or address pain that is intractable to treatments available currently. Opiates, the most powerful drugs to treat pain, pose serious side effects and addictive potential - and sometimes are ineffective. Metabolic or diet-based therapies could offer new, effective analgesic strategies, and initial evidence suggests that ketogenic diets can alleviate pain and inflammation. This proposal tests the efficacy of ketogenic diets in reducing acute and inflammatory pain, and tests the role of adenosine A1 receptors in these effects. Ketogenic diets are very high in fat, with restricted protein and very low carbohydrate content. They were first developed to treat epilepsy based on historical evidence that fasting reduced seizures: a ketogenic diet mimics the metabolic state of fasting by decreasing metabolism of glucose and increasing metabolism of ketones. In basic research and clinical studies the ketogenic diet has shown proven benefits in epilepsy; it has also demonstrated basic research potential for neuroprotection in several types of acute and chronic brain injuries. Furthermore, a number of biochemical consequences of the metabolic changes induced by a ketogenic diet should elevate pain thresholds and reduce inflammatory pain. In support of this, our initial work in rats demonstrated that a ketogenic diet can reduce inflammation and reduce sensitivity to thermal pain. We have also shown that a ketogenic diet can reduce seizures and decrease excitability via adenosine A1 receptors, a known anticonvulsant and neuroprotective mechanism. This proposal's central hypothesis is that ketogenic diets will alleviate pain and inflammation by activating adenosine A1 receptors. Multiple lines of evidence support this hypothesis, yet the treatment of diverse types of pain with ketogenic diets, and the involvement of adenosine in these effects, remains largely untested. The present objective is to test the efficacy and adenosine-based mechanisms of ketogenic diets in multiple models of acute pain (Specific Aim 1) and inflammatory pain (Specific Aim 2) in normal mice and mice with altered adenosine signaling. Testing these hypotheses in well-established animal models is feasible and may offer a breakthrough into metabolic and/or adenosine-based pain treatments that are both effective and non-addictive. In parallel with research goals, our research program supports extensive student training opportunities and enhances the institution's productive, year-round science community.